This application is for renewal of a grant that we have had since 2001. Its purpose is to understand how interactions of CREB and kappa-opioid receptor (KOR) systems in the nucleus accumbens shell (NAs) affect behavior in the context of mood and anxiety disorders. Our 9 years of support has led to discoveries that have had a significant impact on the field: (i) stress activates CREB in the NAs;(ii) elevated CREB function in the NAs triggers depressive-like behaviors;(iii) depressive-like behaviors are induced by CREB-mediated increases in dynorphin actions at KORs;(iv) KOR antagonists have antidepressant-like effects;and (v) KOR antagonists have anxiolytic-like effects. Our work has provided new insights on the role of the NAs in encoding rewarding and aversive states, and led directly to drug development efforts in academia and industry. Our over-arching hypothesis is that stress-induced CREB activation in the NAs increases dynorphin expression, which enhances feedback inhibition of the mesocorticolimbic system. This process triggers behaviors characteristic of depressive and, as new evidence suggests, anxiety-related disorders. Our continuing studies are designed to determine how modifications to this CREB-KOR cascade can cause and protect against the persistent effects of stress, using models that quantify key signs of depression and co-morbid disorders. In Aim 1, we will test the hypothesis that elevated CREB function in the NAs produces behavioral signs common to depressive and frequently co-morbid anxiety disorders such as post-traumatic stress disorder (PTSD). We will use an attention test to examine if elevated CREB in the NAs produces deficits in concentration and decision-making that are hallmark signs of major depression and PTSD. We will also use an inhibition-of-fear test to examine if elevated CREB in the NAs produces deficits in sensitivity to safety signals that characterize PTSD but not depression. In Aim 2, we will test the hypothesis that disruption of KOR function in the mesocorticolimbic system prevents the development of depressive and anxiety-related behaviors. We have made a line of mice in which the KOR gene is floxed, and found that ablation of KORs in all brain areas expressing dopamine uptake transporter (DAT) attenuates stress-related behavioral adaptations. We will use viral vectors to determine if further restriction of KOR ablation to the mesocorticolimbic system during adulthood produces similar resistance to stress. We will use tests (fear conditioning;intracranial self- stimulation) that quantify hallmark signs of depression and anxiety while providing insight on any non-specific effects of our manipulations. In Aim 3, we will test the hypothesis that disruption of KOR function prevents stress effects via actions that involve reduced sensitivity to corticotropin releasing factor (CRF), and that the long-lasting anti-stress effects of KOR antagonists require activation of c-Jun N-terminal kinase (JNK). We will also test the hypothesis that KOR disruption blocks stress-induced alterations in microRNA (miR) expression in the mesocorticolimbic system. This work may provide a basis for improved diagnostics and therapeutics. PUBLIC HEALTH RELEVANCE: This research examines the mechanisms by which stress-induced alterations in the function of the transcription factor CREB and kappa-opioid receptor (KOR) systems trigger depressive and anxiety-related behavior. Our proposed studies are designed to determine how modifications to this CREB-KOR cascade can cause and protect against the persistent effects of stress, using animal models that quantify hallmark signs of depression and anxiety disorders in humans. This work may provide a basis for improved diagnosis, treatment, and prevention of mental illness.